This application outlines a 4 year plan for the development of a career in medical science within the Division of Infectious Disease at the UCLA School of Medicine. Its Principal Investigator has completed training in Internal Medicine and graduate work in the field of medical virology. As a fellow in the Division of Infectious Diseases and member of the UCLA Subspecialty Training and Advanced Research (STAR) program she now details a plan to expand her knowledge and skills in the area of medical virology and immunology in order to become an independent investigator. The proposed program will be carried out under the mentorship of Dr. Otto Yang, a very well-respected, successful member of both the Division of Infectious Diseases and Microbiology, Immunology, and Medical Genetics. Dr. Yang has successfully supervised post-doctoral fellows and graduate students and is an expert in the field of HIV immunology. In particular his research group is a leader in the study of cytotoxic T lymphocyte (CTL) responses to HIV-1 infection. The UCLA research community with its numerous resources and opportunites will provide an excellent environment for the completion of the proposed research plan. The plan focuses on investigating factors influencing the HIV-1 accessory protein Nefs ability to mediate evasion of CTL immune responses. Previous studies by Dr. Yang and others showed that Nef down-regulates MHC Class I on infected cells making them less sensitive to killing by CTLs. The specific aims to be addressed include the following: 1. What factors affect the influence of Nef-mediated MHC-I downregulation on HIV-1 resistance to CTL? 2. What are the impacts of Nef-specific and non-Nef-specific CTLs on Nefs MHC down-regulatory function? 3. What are the relative selective pressures exerted by Nef-specific and non-Nef-specific CTLs on Nef sequence evolution? A combination of in vitro and in vivo methods will be utilized in order to explore the balance between host immune forces which favor the loss of Nefs function and viral forces which favor the retention of Nefs ability to down-regulate MHC I and thus evade CTL killing. The results of these studies are anticipated to further our knowledge of how the immune system works to control HIV-1 infection. This knowledge will help in the ongoing quest for an effective vaccine against HIV.